Cellular/Molecular

Although mutations cause some forms of Parkinson's disease (PD), most cases have no known genetic linkage and are thought to be triggered by environmental factors. Nonetheless, several pathological processes—oxidative stress, mitochondrial dysfunction, impaired proteolysis, and inflammation—appear to be involved in both genetic and sporadic PD, and the primacy of each of these processes may vary across individuals. Imam et al. found that the tyrosine kinase c-Abl, which is activated by oxidative stress, phosphorylates parkin, a protein involved in protein degradation that is mutated in rare forms of PD. Phosphorylation of parkin inhibited its ability to tag proteins for degradation and thus led to accumulation of these proteins. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine), a toxin that kills dopamine neurons, activated c-Abl and increased parkin phosphorylation in mouse striatum. Inhibiting c-Abl prevented parkin phosphorylation and loss of striatal dopamine. Tyrosine phosphorylation of parkin was elevated in striatum of PD patients, suggesting that c-Abl activity contributes to sporadic PD.

Development/Plasticity/Repair

Fear conditioning is thought to be mediated by long-term potentiation (LTP) of sensory inputs to principal neurons in the lateral nucleus of the amygdala (LA). These neurons receive converging auditory and somatosensory inputs and project to the amygdala's central nucleus, which projects to brain regions that produce fear responses. Morozov et al. expressed channelrhodopsin in temporal association cortical (TeA) neurons, which convey auditory information to LA via the external capsule (EC). Photostimulation of TeA axons excited not only LA principal neurons, but also putative paracapsular intercalated neurons within the EC, which send inhibitory projections to the LA. Transecting inputs from the EC, which eliminated inhibitory inputs from intercalated neurons, facilitated LTP of TeA inputs to LA principal neurons. These results suggest that TeA projections elicit inhibitory and excitatory inputs to the LA, and the inhibitory connections limit LTP of the excitatory synapses. Reduction of this inhibition, e.g., by neuromodulators, might therefore facilitate the formation of fear memories.

Behavioral/Systems/Cognitive

Chronic stress can precipitate depression in humans, and chronic social defeat stress in mice causes depression-like behavioral phenotypes, e.g., social avoidance, weight loss, and reduced performance of pleasurable activities. These behaviors are reversed by chronic treatment with antidepressants in both mice and humans, suggesting that they are mechanistically similar. Stress-induced decreases in social interaction in mice appear to be caused in part by increased firing of dopaminergic neurons in the ventral tegmental area, which results in increased release of brain-derived neurotrophic factor in their target, the nucleus accumbens. Christoffel et al. examined the effects of chronic social defeat stress in the nucleus accumbens, and found it increased the density of stubby (putatively immature) dendritic spines, the frequency of miniature EPSCs, and the activity of IκB kinase, which regulates spine structural plasticity, in susceptible mice. Expression of dominant-negative IκB kinase prevented stress-induced increases in stubby spine density and eliminated post-stress social avoidance.

Neurobiology of Disease

Although Parkinson's disease (PD) probably follows different pathological courses in different individuals, the courses are thought to converge on the activation of apoptotic cascades leading to cell death. Apoptosis typically involves phosphorylation of c-jun N-terminal kinase (JNK) by upstream kinases (such as apoptosis signal-regulating kinase, ASK1) and subsequent activation of transcription factors that regulate cell death genes. Hu et al. found that ASK-1 and JNK were activated in substantia nigra of PD patients and in neurons treated with 6-hydroxydopamine (6-OHDA), a toxin that produces parkinsonism in mice. Knockdown of ASK1 prevented phosphorylation of JNK and increased survival of neurons exposed to 6-OHDA. ASK1 is normally kept inactive in cells by binding to thioredoxin, but oxidation of thioredoxin causes dissociation and activation of ASK1. 6-OHDA caused oxidation of thioredoxin, but this was prevented by overexpression of peroxiredoxin 2 (PRX2). Overexpression of PRX2 in mouse substantia nigra protected dopamine neurons from 6-OHDA-induced death and preserved motor function.